Malignant brain tumors are devastating, with little hope of cure for affected patients. Among heterogeneous cell populations in brain tumors, recent investigations, including our own, have identified a stem cell population, called `brain tumor stem cells (BTSC)'. The cancer stem cell theory dictates that any curative therapy needs to kill or arrest cancer stem cells from expanding, whereas therapies targeted at derivatives of cancer stem cells are not curative. Recent studies, however, have revealed that the current treatments, including radiotherapy and chemotherapy with temozolomide, preferentially kill non-BTSC and fail to eliminate BTSC. It is likely due to the existence of compensatory oncogenic pathways that allow tumor stem cells to escape and survive. In this exploratory grant proposal, we hypothesize that targeted therapeutic strategies, which exploit molecular differences present within heterogeneous populations of brain tumor cells, will lead to the specific eradication of BTSC without causing death of normal cells in the brain. To address this hypothesis, we will take molecularly-targeted approaches against a cell surface protein, CD44. Based on our preliminary data, CD44 is selectively expressed by stem cells within brain tumor cells, in comparison to CD133, the only marker currently adopted to enrich for BTSC. In addition, CD44 plays critical roles in proliferation of BTSC. We will determine whether targeting CD44 in BTSC can arrest malignant brain tumor growth by using both in vitro cultures as well as in vivo xenograft brain tumor model. PUBLIC HEALTH RELEVANCE: The discovery of brain tumor stem cells can shed light on the advanced treatments for patients with malignant brain tumors. In this proposal, we will undertake innovative strategies targeting molecular aberrations in brain tumor stem cells. The successful achievement of this proposal will enable us to launch novel therapeutic approaches for patients with brain tumors.